Methods to mobilize progenitor/stem cells

ABSTRACT

Methods to elevate progenitor and stem cell counts in animal subjects using compounds which bind to the chemokine receptor CXCR4 are disclosed. Preferred embodiments of such compounds are of the formula 
 
Z-linker-Z′  ( 1 ) 
or pharmaceutically acceptable salt thereof wherein Z is a cyclic polyamine containing 9-32 ring members of which 3-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system; 
 
or Z is of the formula  
                 
wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms, Z′ may be embodied in a form as defined by Z above, or alternatively may be of the formula 
 
—N(R)—(CR 2 ) n —X 
wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan; “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 11/269,773 filed 8Nov. 2005, which is a divisional of U.S. Ser. No. 10/209,001 filed 30Jul. 2002 and now U.S. Pat. No. 6,987,102 which claims priority under 35U.S.C. §119(e) to U.S. provisional application Ser. No. 60/382,155 filed20 May 2002 and to Ser. No. 60/309,196 filed 31 Jul. 2001. The contentsof these applications are incorporated herein by reference.

TECHNICAL FIELD

The invention is in the field of therapeutics and medicinal chemistry.More particularly, the invention concerns methods to mobilizeprogenitor/stem cells in subjects by administering certain polyamines.

BACKGROUND ART

Blood cells play a crucial part in maintaining the health and viabilityof animals, including humans. White blood cells include neutrophils,macrophage, eosinophils and basophils/mast cells as well the B and Tcells of the immune system. White blood cells are continuously replacedvia the hematopoietic system, by the action of colony stimulatingfactors (CSF) and various cytokines on stem cells and progenitor cellsin hematopoietic tissues. The nucleotide sequences encoding a number ofthese growth factors have been cloned and sequenced. Perhaps the mostwidely known of these is granulocyte colony stimulating factor (G-CSF)which has been approved for use in counteracting the negative effects ofchemotherapy by stimulating the production of white blood cells andprogenitor cells (peripheral blood stem cell mobilization). A discussionof the hematopoietic effects of this factor can be found, for example,in U.S. Pat. No. 5,582,823, incorporated herein by reference.

Several other factors have been reported to increase white blood cellsand progenitor cells in both human and animal subjects. These agentsinclude granulocyte-macrophage colony stimulating factor (GM-CSF),Interleukin-1 (IL-1), Interleukin-3 (IL-3), Interleukin-8 (IL-8),PIXY-321 (GM-CSF/IL-3 fusion protein), macrophage inflammatory protein,stem cell factor, thrombopoietin and growth related oncogene, as singleagents or in combination (Dale, D., et al., Am. J. of Hematol. (1998)57:7-15; Rosenfeld, C., et al., Bone Marrow Transplantation (1997)17:179-183; Pruijt, J., et al., Cur. Op. in Hematol. (1999) 6:152-158,Broxmeyer, H., et al., Exp. Hematol. (1995) 23:335-340; Broxmeyer, etal., Blood Cells, Molecules and Diseases (1998) 24:14-30; Glaspy, J., etal., Cancer Chemother. Pharmacol. (1996) 38 (suppl): S53-S57;Vadhan-Raj, S., et al., Ann. Intern. Med. (1997) 126:673-81; King, A.,et al., Blood (2001) 97:1534-1542; Glaspy, J., et al., Blood (1997)90:2939-2951).

While endogenous growth factors are pharmacologically effective, thewell known disadvantages of employing proteins and peptides aspharmaceuticals underlies the need to add to the repertoire of suchgrowth factors with agents that are small molecules. In another aspect,such small molecules are advantageous over proteins and peptides whereproduction in large quantities are desired.

A number of cyclic polyamine antiviral agents have been described in aseries of U.S. patents and applications over the last several years.These patents, U.S. Pat. Nos. 5,021,409; 6,001,826; 5,583,131;5,698,546; and 5,817,807 are incorporated herein by reference. Alsoincorporated by reference are PCT publications WO 00/02870 based on anapplication filed 8 Jul. 1998 and WO 01/44229, based on an applicationfiled 17 Dec. 1999, which describe additional compounds. Thesepublications describe the structural characteristics of the cyclicpolyamine antiviral agents.

The structural characteristics of a number of non-cyclic amine antiviralagents have also been described in a series of U.S. applications, nowpublished as PCT publications. These publications, WO 00/56729, based onan application filed 24 Mar. 2000; WO 02/22600, based on applicationsfiled 15 and 20 Sep. 2000; WO 02/22599, based on applications filed 15and 22 Sep. 2000 as well as WO 02/34745 published 2 May 2002, areincorporated herein by reference in their entirety.

In addition, improved methods for preparation of some of the cyclicpolyamine compounds are described in U.S. Pat. Nos. 5,612,478;5,756,728; 5,801,281; and 5,606,053 and PCT publication WO 02/26721,based on an application filed 29 Sep. 2000. The disclosures of theseU.S. documents are also incorporated herein by reference in theirentirety.

We have previously found, and have disclosed in PCT publication WO02/58653, based on an application filed 1 Feb. 2000, that some of thepolyamine antiviral agents described in the above mentioned publicationshave the effect of increasing the white blood cell count. It has nowbeen found that the polyamine antiviral agents described in theabove-mentioned publications also have the effect of increasingprogenitor cells and/or stem cells.

The development and maturation of blood cells is a complex process.Mature blood cells are derived from hematopoietic precursor cells(progenitor) cells and stem cells present in specific hematopoietictissues including bone marrow. Within these environments hematopoieticcells proliferate and differentiate prior to entering the circulation.The chemokine receptor CXCR4 and its natural ligand stromal cell derivedfactor-1 (SDF-1) appear to be important in this process (for reviews seeMaekawa, T., et al., Internal Med. (2000) 39:90-100; Nagasawa, T., etal., Int. J. Hematol. (2000) 72:408-411). This is demonstrated byreports that CXCR4 or SDF-1 knock-out mice exhibit hematopoietic defects(Ma, Q., et al., Proc. Natl. Acad. Sci USA (1998) 95:9448-9453;Tachibana, K., et al., Nature (1998) 393:591-594; Zou, Y-R., et al.,Nature (1998) 393:595-599). It is also known that CD34+ progenitor cellsexpress CXCR4 and require SDF-1 produced by bone marrow stromal cellsfor chemoattraction and engraftment (Peled, A., et al., Science (1999)283:845-848) and that in vitro, SDF-1 is chemotactic for both CD34+cells (Aiuti, A., et al., J. Exp. Med. (1997) 185:111-120; Viardot, A.,et al., Ann. Hematol. (1998) 77:194-197) and for progenitor/stem cells(Jo, D-Y., et al, J. Clin. Invest. (2000) 105:101 -111). SDF-1 is alsoan important chemoattractant, signaling via the CXCR4 receptor, forseveral other more committed progenitors and mature blood cellsincluding T-lymphocytes and monocytes (Bleul, C., et al., J. Exp. Med.(1996) 184:1101-1109), pro-and pre-B lymphocytes (Fedyk, E. R., et al.,J. Leukoc. Biol. (1999) 66:667-673; Ma, Q., et al., Immunity (1999)10:463-471) and megakaryocytes (Hodohara, K., et al., Blood (2000)95:769-775; Riviere, C., et al., Blood (1999) 95:1511-1523; Majka, M.,et al., Blood (2000) 96:4142-4151; Gear, A., et al., Blood (2001)97:937-945; Abi-Younes, S., et al., Circ. Res. (2000) 86:131-138).

Thus, in summary, it appears that SDF-1 is able to control thepositioning and differentiation of cells bearing CXCR4 receptors whetherthese cells are stem cells (i.e., cells which are CD34+) and/orprogenitor cells (which result in formation of specified types ofcolonies in response to particular stimuli; that can be CD34+ or CD34−)or cells that are somewhat more differentiated.

Recently, considerable attention has been focused on the number of CD34+cells mobilized in the pool of peripheral blood progenitor cells usedfor autologous stem cell transplantation. The CD34+ population is thecomponent thought to be primarily responsible for the improved recoverytime after chemotherapy and the cells most likely responsible forlong-term engraftment and restoration of hematopoiesis (Croop, J. M., etal., Bone Marrow Transplantation (2000) 26:1271-1279). The mechanism bywhich CD34+ cells re-engraft may be due to the chemotactic effects ofSDF-1 on CXCR4 expressing cells (Voermans, C., Blood, 2001, 97, 799-804;Ponomaryov, T., et al., J. Clin. Invest. (2000) 106:1331-1339). Morerecently, adult hematopoietic stem cells were shown to be capable ofrestoring damaged cardiac tissue in mice (Jackson, K., et al., J. Clin.Invest. (2001) 107:1395-1402; Kocher, A., et al., Nature Med. (2001)7:430-436).

Thus, the role of the CXCR4 receptor in managing cell positioning anddifferentiation has assumed considerable significance.

Citation of the above documents is not intended as an admission that anyof the foregoing is pertinent prior art. All statements as to the dateor representation as to the contents of these documents is based on theinformation available to the applicants and does not constitute anyadmission as to the correctness of the dates or contents of thesedocuments. Further, all documents referred to throughout thisapplication are incorporated in their entirety by reference herein.

DISCLOSURE OF THE INVENTION

The invention is directed to methods of treating animal subjects, inparticular, veterinary and human subjects, to enhance the number ofprogenitor cells and/or stem cells. The progenitor and/or stem cells maybe harvested and used in cell transplantation. The methods of theinvention employ polyamines including those described in the patents andpublications incorporated hereinabove by reference.

In one aspect, therefore, the invention is directed to a method toelevate the progenitor cells and/or stem cells, in a subject, whichmethod comprises administering to said subject an amount of a compoundof formula (1) or of a pharmaceutical composition thereof effective toelevate progenitor cell and/or stem cell levels. In one embodiment, bonemarrow progenitor and/or stem cells are mobilized for myocardial repair.

The methods of the invention also include treatment of cell populationsex vivo with the compounds of formula (1) and introducing the treatedpopulations into a compatible subject. The compounds of formula (1) maybe used alone or in combination with other compounds and compositions toenhance the population of stem cells and/or progenitor cells in theperipheral blood. An enhanced production of white blood cells in thebone marrow may result as well.

In additional aspects, the invention is directed to pharmaceuticalcompositions containing the compound of formula (1) for use in effectingan elevation of progenitor cells and/or stem cells in animal subjects.

The compounds of formula (1) are of the formula:Z-linker-Z′  (1)

wherein Z is a cyclic polyamine containing 9-32 ring members of which2-8 are nitrogen atoms, said nitrogen atoms separated from each other byat least 2 carbon atoms, and wherein said heterocycle may optionallycontain additional heteroatoms besides nitrogen and/or may be fused toan additional ring system;

or Z is of the formula

wherein A comprises a monocyclic or bicyclic fused ring systemcontaining at least one N and B is H or an organic moiety of 1-20 atoms;

Z′ may be embodied in a form as defined by Z above, or alternatively maybe of the formula—N(R)—(CR₂)_(n)—X

wherein each R is independently H or straight, branched or cyclic alkyl(1-6C),

n is 1 or 2, and

X is an aromatic ring, including heteroaromatic rings, or is amercaptan;

“linker” represents a bond, alkylene (1-6C) or may comprise aryl, fusedaryl, oxygen atoms contained in an alkylene chain, or may contain ketogroups or nitrogen or sulfur atoms.

The preferred forms of the compounds of the invention are discussedbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a graph of obtaining myeloid progenitors in response totreatment with1,1′-[1,4-phenylene-bis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane(AMD3100) in combination with macrophage inflammatory protein afteradministration of G-CSF.

MODES OF CARRYING OUT THE INVENTION

The compounds useful in the invention are of the general formula setforth as formula (1) above. Certain embodiments are preferred; includedamong these are the compounds set forth in the above-incorporated U.S.patents and other patent documents.

The cyclic polyamine and non-cyclic amine antiviral agents described inthe above-mentioned documents inhibit HIV replication via inhibition ofCXCR4, the co-receptor required for fusion and entry of T-tropic HIVstrains, and also inhibit the binding and signaling induced by thenatural ligand, the chemokine SDF-1. While not wishing to be bound byany theory, the compounds of formula (1) which inhibit the binding ofSDF-1 to CXCR4 effect an increase in stem and/or progenitor cells byvirtue of such inhibition. Enhancing the stem and/or progenitor cells inblood is helpful in treatments to alleviate the effects of protocolsthat adversely affect the bone marrow, such as those that result inleukopenia. These are known side-effects of chemotherapy andradiotherapy. The compounds of formula (1) also enhance the success ofbone marrow transplantation, enhance wound healing and burn treatment,and aid in restoration of damaged organ tissue. They also combatbacterial infections that are prevalent in leukemia. The compounds offormula (1) are used to mobilize and harvest CD34+ cells via apheresiswith and without combinations with other mobilizing factors. Theharvested cells are used in treatments requiring stem celltransplantations.

As used herein, the term “progenitor cells” refers to cells that, inresponse to certain stimuli, can form differentiated hematopoietic ormyeloid cells. The presence of progenitor cells can be assessed by theability of the cells in a sample to form colony-forming units of varioustypes, including, for example, CFU-GM (colony-forming units,granulocyte-macrophage); CFU-GEMM (colony-forming units,multipotential); BFU-E (burst-forming units, erythroid); HPP-CFC (highproliferative potential colony-forming cells); or other types ofdifferentiated colonies which can be obtained in culture using knownprotocols.

As used herein, “stem” cells are less differentiated forms of progenitorcells. Typically, such cells are often positive for CD34. Some stemcells do not contain this marker, however. These CD34+ cells can beassayed using fluorescence activated cell sorting (FACS) and thus theirpresence can be assessed in a sample using this technique.

In general, CD34+ cells are present only in low levels in the blood, butare present in large numbers in bone marrow. While other types of cellssuch as endothelial cells and mast cells also may exhibit this marker,CD34 is considered an index of stem cell presence.

In general, in compounds of formula (1), preferred embodiments of Z andZ′ are cyclic polyamine moieties having from 9-24C that include 3-5nitrogen atoms. Particularly preferred are1,5,9,13-tetraazacyclohexadecane; 1,5,8,11,14-pentaazacyclohexadecane;1,4,8,11-tetraazacylotetradecane; 1,5,9-triazacyclododecane;1,4,7,10-tetraazacyclododecane; and the like, including such cyclicpolyamines which are fused to an additional aromatic or heteroaromaticrings and/or containing a heteroatom other than nitrogen incorporated inthe ring. Embodiments wherein the cyclic polyamine contains a fusedadditional cyclic system or one or more additional heteroatoms aredescribed in U.S. Pat. No. 5,698,546 and WO 01/44229 incorporatedhereinabove by reference. Also preferred are

3,7,11,17-tetraazabicyclo(13.3.1)heptadeca-1(17),13,15-triene;

4,7,10,17-tetraazabicyclo(13.3.1)heptadeca-1(17),13,15-triene;

1,4,7,10-tetraazacyclotetradecane; 1,4,7-triazacyclotetradecane; and

4,7,10-triazabicyclo(13.3.1)heptadeca-1(17),13,15-triene.

When Z′ is other than a cyclic polyamine as defined in Z, its preferredembodiments are set forth in U.S. Pat. No. 5,817,807, also incorporatedherein by reference.

Preferred forms where

Z is of the formula

wherein A comprises a monocyclic or bicyclic fused ring systemcontaining at least one N and B is H or an organic moiety of 1-20 atomsare disclosed in WO 00/56729; WO 02/22600; WO 02/34745; and WO 02/22599cited above and all incorporated herein by reference.

Preferred forms of the linker moiety include those wherein the linker isa bond, or wherein the linker includes an aromatic moiety flanked byalkylene, preferably methylene moieties. Preferred linking groupsinclude the methylene bracketed forms of 1,3-phenylene, 2,6-pyridine,3,5-pyridine, 2,5-thiophene, 4,4′-(2,2′-bipyrimidine);2,9-(1,10-phenanthroline) and the like. A particularly preferred linkeris 1,4-phenylene-bis-(methylene).

Particularly preferred embodiments of the compound of the formula (1)include 2,2′-bicyclam; 6,6′-bicyclam; the embodiments set forth in U.S.Pat. Nos. 5,021,409, and 6,001,826, and in particular1,1′-[1,4-phenylene-bis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane,set forth in U.S. Pat. No. 5,583,131, and designated herein AMD3100.

Other preferred embodiments include

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-aminomethyl)pyridine;

7,7′-[1,4-phenylenebis(methylene)]bis-4,7,10,17-tetraazabicyclo-[13.3.1]heptadeca-1(17),13,15-triene;

7,7′-[1,4-phenylenebis(methylene)]bis-3,7,11,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-triene;

1,1′-[1,3-phenylenebis(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecane;

1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecane;

1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane;

1,1′-[1,3-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane;

11,11′-(1,2-propanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

N-[4-(1,4,7-triazacyclotetra-decane)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,7,10-triazabicyclo[13.3.1]heptadeca-1(17),13,15-triene)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,7,10,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-triene)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-[4,7,10,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-triene]-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

3,3′-(bis-1,5,9,13-tetraazacyclohexadecane);

3,3′-(bis-1,5,8,11,14-pentaazacyclohexadecane), methylene (orpolymethylene) di-1-N-1,4,8,11-tetraazacyclotetradecane;

3,3′-bis-1,5,9,13,-tetraazacyclohexadecane;

3,3′-bis-1,5,8,11,14-pentaazacyclohexadecane;

5,5′-bis-1,4,8,11-tetraazacyclotetradecane;

2,5′-bis-1,4,8,11-tetraazacyclotetradecane;

2,6′-bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-ethanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-propanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-butanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-pentanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-hexanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

3,3′-bis-1,5,9,13-tetraazacyclohexadecane;

3,3′-bis-1,5,8,11,14-pentaazacyclohexadecane;

5,5′-bis-1,4,8,11-tetraazacyclotetradecane;

2,5′-bis-1,4,8,11-tetraazacyclotetradecane;

2,6′-bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-ethanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-propanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-butanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-pentanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-(1,2-hexanediyl)bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[1,3-phenylenebis(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecane;

1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecane;

1,1′-[3,3′-biphenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

11,11′-[1,4-phenylene-bis-(methylene)]-bis-1,4,7,11-tetraazacyclotetradecane;

1,11′-[1,4-phenylene-bis(methylene)]-1,4,8,11-tetraazacyclotetradecane;

1,1′-[2,6-pyridine-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

1,1-[3,5-pyridine-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[2,5-thiophene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[4,4′-(2,2′-bipyridine)-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[2,9-(1,10-phenanthroline)-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[1,3-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane;

1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane;

1,1′-[5-nitro-1,3-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[2,4,5,6-tetrachloro-1,3-phenyleneis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[2,3,5,6-tetrafluoro-1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[1,4-naphthylene-bis-(methylene)]bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[1,3-phenylenebis-(methylene)]bis-1,5,9-triazacyclododecane;

1,1′-[1,4-phenylene-bis-(methylene)]-1,5,9-triazacyclododecane;

1,1′-[2,5-dimethyl-1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[2,5-dichloro-1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[2-bromo-1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

1,1′-[6-phenyl-2,4-pyridinebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane;

7,7′-[1,4-phenylene-bis(methylene)]bis-3,7,11,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-triene;

7,7′-[1,4-phenylene-bis(methylene)]bis[15-chloro-3,7,11,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-triene];

7,7′-[1,4-phenylene-bis(methylene)]bis[15-methoxy-3,7,11,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-triene];

7,7′-[1,4-phenylene-bis(methylene)]bis-3,7,11,17-tetraazabicyclo[13.3.1]-heptadeca-13,16-triene-15-one;

7,7′-[1,4-phenylene-bis(methylene)]bis-4,7,10,17-tetraazabicyclo[13.3.1]-heptadeca-1(17),13,15-triene;

8,8′-[1,4-phenylene-bis(methylene)]bis-4,8,12,19-tetraazabicyclo[15.3.1]nonadeca-1(19),15,17-triene;

6,6′-[1,4-phenylene-bis(methylene)]bis-3,6,9,15-tetraazabicyclo[11.3.1]pentadeca-1(15),11,13-triene;

6,6′-[1,3-phenylene-bis(methylene)]bis-3,6,9,15-tetraazabicyclo[11.3.1]pentadeca-1(15),11,13-triene;

17,17′-[1,4-phenylene-bis(methylene)]bis-3,6,14,17,23,24-hexaazatricyclo[17.3.1.1^(8,12)]tetracosa-1(23),8,10,12(24),19,21-hexaene;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(amino-methyl)pyridine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-N-methyl-2-(aminomethyl)pyridine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-4-)amino-methyl)pyridine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-3-(amino-methyl)pyridine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-(2-amino-methyl-5-methyl)pyrazine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(amino-ethyl)pyridine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(amino-methyl)thiophene;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(amino-ethyl)mercaptan;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-amino-benzylamine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-4-amino-benzylamine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-4-(amino-ethyl)imidazole;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-benzylamine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-purine;

N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-4-phenylpiperazine;

N-[4-(1,4,7-triazacyclotetra-decanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,7,10,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,7,10-triazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-[4,7,10-triazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl]-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[1-(1,4,7-triazacyclotetra-decanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-[4,7,10,17-tetraazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl]-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[3-(3,6,17-triazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[3-(3,6,17-triazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl)-1,3-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(4,7,17-triazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,7,17-triazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[6-(3,6,9-triazabicyclo[11.3.1]pentadeca-1(15),11,13-trienyl)-1,3-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,10,17-triazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(1,7-diazacyclotetradecanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[7-(4,10-diazabicyclo[13.3.1]heptadeca-1(17),13,15-trienyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(11-fluoro-1,4,7-triazacyclotetradecanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(11,11-difluoro-1,4,7-triazacyclotetradecanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(1,4,7-triazacyclotetradecan-2-one)-yl))-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[12-(5-oxa-1,9-diazacyclotetradecanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(11-oxa-1,7-diazacyclotetradecanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(11-thia-1,7-diazacyclotetradecanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(11-sulfoxo-1,7-diazacyclotetradecanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(11-sulfono-1,7-diazacyclotetradecanyl)-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-[4-(1,4,7-triazacyclotetradecan-3-one)-yl))-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine;

N-(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(2-pyridinylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(2-phenyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N′-(2-phenyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-5-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-5-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[(2-amino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1H-imidazol-4-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(2-quinolinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(2-(2-naphthoyl)aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[(S)-(2-acetylamino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[(S)-(2-acetylamino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[3-((2-naphthalenylmethyl)amino)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-(S)-pyrollidinylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-(R)-pyrollidinylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[3-pyrazolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-pyrrolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-thiopheneylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

N-(2-pyridinylmethyl)-N′-[2-thiazolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-furanylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(phenylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-3-pyrrolidinyl-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

N-(2-pyridinylmethyl)-N′-4-piperidinyl-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(phenyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1-methyl-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(7-methoxy-3,4-dihydronaphthalenyl)-1-(aminomethyl)-4-benzamide;

N-(2-pyridinylmethyl)-N′-(6-methoxy-3,4-dihydronaphthalenyl)-1-(aminomethyl)-4-benzamide;

N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(2-naphthalenylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-(isobutylamino)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(2-pyridinylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(2-furanylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(2-guanidinoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[bis-[(2-methoxy)phenylmethyl]amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-4-ylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-(phenylureido)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[[N″-(n-butyl)carboxamido]methyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(carboxamidomethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[(N″-phenyl)carboxamidomethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(carboxymethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(phenylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt);

N-(2-pyridinylmethyl)-N′-(5-nitro-1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[(1H)-5-azabenzimidazol-2-ylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N-(4-phenyl-1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-[2-(2-pyridinyl)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(2-benzoxazolyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(trans-2-aminocyclohexyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(2-phenylethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(3-phenylpropyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N′-(trans-2-aminocyclopentyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-glycinamide;

N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-alaninamide;

N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-aspartamide;

N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-pyrazinamide;

N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-prolinamide;

N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-lysinamide;

N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-benzamide;

N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-picolinamide;

N′-benzyl-N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-urea;

N′-phenyl-N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-urea;

N-(6,7,8,9-tetrahydro-5H-cyclohepta[bacteriapyridin-9-yl)-4-[[(2-pyridinylmethyl)amino]methyl]benzamide;

N-(5,6,7,8-tetrahydro-8-quinolinyl)-4-[[(2-pyridinylmethyl)amino]methyl]benzamide;

N,N′-bis(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[bacteriapyridin-9-yl)-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N′-(6,7-dihydro-5H-cyclopenta[bacteriapyridin-7-yl)-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N′-[(5,6,7,8-tetrahydro-8-quinolinyl)methyl]-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N′[(6,7-dihydro-5H-cyclopenta[bacteriapyridin-7-yl)methyl]-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N-(2-methoxyethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(2-pyridinylmethyl)-N-[2-(4-methoxyphenyl)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-1,4-(5,6,7,8-tetrahydro-8-quinolinyl)benzenedimethanamine;

N-[(2,3-dimethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N-[1-(N″-phenyl-N″-methylureido)-4-piperidinyl]-1,3-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N-[N″-p-toluenesulfonylphenylalanyl)-4-piperidinyl]-1,3-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N-[1-[3-(2-chlorophenyl)-5-methyl-isoxazol-4-oyl]-4-piperidinyl]-1,3-benzenedimethanamine;

N-[(2-hydroxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[bacteriapyridin-9-yl)-1,4-benzenedimethanamine;

N-[(4-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[bacteriapyridin-9-yl)-1,4-benzenedimethanamine;

N-[(4-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(4-acetamidophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(4-phenoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[bacteriapyridin-9-yl)-1,4-benzenedimethanamine;

N-[(1-methyl-2-carboxamido)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(4-benzyloxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[bacteriapyridin-9-yl)-1,4-benzenedimethanamine;

N-[(thiophene-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[bacteriapyridin-9-yl)-1,4-benzenedimethanamine;

N-[1-(benzyl)-3-pyrrolidinyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[[1-methyl-3-(pyrazol-3-yl)]propyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[1-(phenyl)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(3,4-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[1-benzyl-3-carboxymethyl-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(3,4-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(3-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[[1-methyl-2-(2-tolyl)carboxamido]ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(1,5-dimethyl-2-phenyl-3-pyrazolinone-4-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(4-propoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(1-phenyl-3,5-dimethylpyrazolin-4-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[1H-imidazol-4-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(3-methoxy-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[(3-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[(3-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(5-ethylthiophene-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(5-ethylthiophene-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(2,6-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[(2,6-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(2-difluoromethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(2-difluoromethoxyphenylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(1,4-benzodioxan-6-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N-[1-(N″-phenyl-N″-methylureido)-4-piperidinyl]-1,4-benzenedimethanamine;

N,N′-bis(2-pyridinylmethyl)-N-[N′-p-toluenesulfonylphenylalanyl)-4-piperidinyl]-1,4-benzenedimethanamine;

N-[1-(3-pyridinecarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[1-(cyclopropylcarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[1-(1-phenylcyclopropylcarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-(1,4-benzodioxan-6-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[1-[3-(2-chlorophenyl)-5-methyl-isoxazol-4-carboxamido]-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[1-(2-thiomethylpyridine-3-carboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[(2,4-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(1-methylpyrrol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(2-hydroxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(3-methoxy-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(3-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[2-(N″-morpholinomethyl)-1-cyclopentyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[(1-methyl-3-piperidinyl)propyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-(1-methylbenzimidazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[1-(benzyl)-3-pyrrolidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[[(1-phenyl-3-(N″-morpholino)]propyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[1-(iso-propyl)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[1-(ethoxycarbonyl)-4-piperidinyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(1-methyl-3-pyrazolyl)propyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[1-methyl-2-(N″,N″-diethylcarboxamido)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[(1-methyl-2-phenylsulfonyl)ethyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(2-chloro-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[1-methyl-2-[N″-(4-chlorophenyl)carboxamido]ethyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(1-acetoxyindol-3-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[(3-benzyloxy-4-methoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(3-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-[(8-hydroxy)-2-quinolylmethyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(2-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[(4-acetamidophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[1H-imidazol-2-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-(3-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(2-thiazolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(4-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[(5-benzyloxy)benzo[b]pyrrol-3-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-(1-methylpyrazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[(4-methyl)-1H-imidazol-5-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[[(4-dimethylamino)-1-napthalenyl]methyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[1,5-dimethyl-2-phenyl-3-pyrazolinone-4-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[1-[(1-acetyl-2-(R)-prolinyl]-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[1-[2-acetamidobenzoyl-4-piperidinyl]-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(2-cyano-2-phenyl)ethyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[(N″-acetyltryptophanyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(N″-benzoylvalinyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(4-dimethylaminophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-(4-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(1-methylbenzimadazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;

N-[1-butyl-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[1-benzoyl-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[1-(benzyl)-3-pyrrolidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[(1-methyl)benzo[b]pyrrol-3-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[1H-imidazol-4-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;

N-[1-(benzyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[1-methylbenzimidazol-2-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[(2-phenyl)benzo[b]pyrrol-3-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamine;

N-[(6-methylpyridin-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;

N-(3-methyl-1H-pyrazol-5-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;

N-[(2-methoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;

N-[(2-ethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,3-benzenedimethanamine;

N-(benzyloxyethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;

N-[(2-ethoxy-1-naphthalenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;

N-[(6-methylpyridin-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;

1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]guanidine;

N-(2-pyridinylmethyl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1,4-benzenedimethanamine;

1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]homopiperazine;

1-[[3-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]homopiperazine;

trans andcis-1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,5-piperidinediamine;

N,N′-[1,4-phenylenebis(methylene)]bis-4-(2-pyrimidyl)piperazine;

1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-1-(2-pyridinyl)methylamine;

2-(2-pyridinyl)-5-[[(2-pyridinylmethyl)amino]methyl]-1,2,3,4-tetrahydroisoquinoline;

1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diaminopyrrolidine;

1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diacetylaminopyrrolidine;

8-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-2,5,8-triaza-3-oxabicyclo[4.3.0]nonane;and

8-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-2,5,8-triazabicyclo[4.3.0]nonane.

Methods to synthesize the compounds useful in the method of theinvention are set forth in the U.S. patents and application incorporatedhereinabove by reference.

As provided above, AMD3100 is an antagonist with the CXCR4 chemokinereceptor (Gerlach, et al., J. Biol. Chem. (2001) 276:14153-14160). Thiscompound interferes with the binding of bone marrow stromal cell derivedSDF-1 with CXCR4 on stem cells which leads to the release ofhematopoietic stem cells from bone marrow into the circulation(Broxmeyer, et al., Blood (2001) 98:811a (Abstract)). In a Phase 1 studyat the University of Washington, Seattle, a single dose of 80 μg/kg ofAMD3100 resulted in a WBC count of 17,000/μl and a peak 6-fold increasein circulating CD34+ progenitor/stem cells at the 6 hour time point(Liles, et al., Blood (2001) 98:737a (Abstract)). In another recentstudy mice were injected with rhG-CSF and recombinant rat Stem CellFactor (rrSCF) in order to mobilize large numbers of bone marrow stemcells into the circulation and then we induced a heart attack. Thecombination of rrSCF and rhG-CSF provides a peak number of circulatingstem cells after 5 daily injections. At 27 days post surgery there was a68% improvement in survival in the treated group versus the controls. Atthis time the dead tissue was replaced with regenerating myocardium andall functional parameters tested were improved compared with controls(Orlic, et al., PNAS (2001) 98:10344-10349).

The compounds of the invention may be prepared in the form of prodrugs,i.e., protected forms which release the compounds of the invention afteradministration to the subject. Typically, the protecting groups arehydrolyzed in body fluids such as in the bloodstream thus releasing theactive compound or are oxidized or reduced in vivo to release the activecompound. A discussion of prodrugs is found in Smith and WilliamsIntroduction to the Principles of Drug Design, Smith, H. J.; Wright,2^(nd) ed., London (1988).

The compounds of the invention, as they are polyamines, may beadministered prepared in the forms of their acid addition salts or metalcomplexes thereof. Suitable acid addition salts include salts ofinorganic acids that are biocompatible, including HCl, HBr, sulfuric,phosphoric and the like, as well as organic acids such as acetic,propionic, butyric and the like, as well as acids containing more thanone carboxyl group, such as oxalic, glutaric, adipic and the like.Typically, at physiological pH, the compounds of the invention will bein the forms of the acid addition salts. Particularly preferred are thehydrochlorides. In addition, when prepared as purified forms, thecompounds may also be crystallized as the hydrates.

The compounds of the invention may be administered as sole activeingredients, as mixtures of various compounds of formula (1), and/or inadmixture with additional active ingredients that are therapeutically ornutritionally useful, such as antibiotics, vitamins, herbal extracts,anti-inflammatories, glucose, antipyretics, analgesics,granulocyte-macrophage colony stimulating factor (GM-CSF), Interleukin-1(IL-1), Interleukin-3 (IL-3), Interleukin-8 (IL-8), PIXY-321(GM-CSF/IL-3 fusion protein), macrophage inflammatory protein, stem cellfactor, thrombopoietin, growth related oncogene or chemotherapy and thelike.

The compounds of the invention may be formulated for administration toanimal subject using commonly understood formulation techniques wellknown in the art. Formulations which are suitable for particular modesof administration and for compounds of the type represented by those offormula (1) may be found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa.

Preferably, the compounds are administered by injection, most preferablyby intravenous injection, but also by subcutaneous or intraperitonealinjection, and the like. Additional parenteral routes of administrationinclude intramuscular and intraarticular injection. For intravenous orparenteral administration, the compounds are formulated in suitableliquid form with excipients as required. The compositions may containliposomes or other suitable carriers. For injection intravenously, thesolution is made isotonic using standard preparations such as Hank'ssolution.

Besides injection, other routes of administration may also be used. Thecompounds may be formulated into tablets, capsules, syrups, powders, orother suitable forms for administration orally. By using suitableexcipients, these compounds may also be administered through the mucosausing suppositories or intranasal sprays. Transdermal administration canalso be effected by using suitable penetrants and controlling the rateof release.

The formulation and route of administration chosen will be tailored tothe individual subject, the nature of the condition to be treated in thesubject, and generally, the judgment of the attending practitioner.

Suitable dosage ranges for the compounds of formula (1) vary accordingto these considerations, but in general, the compounds are administeredin the range of about 0.1 μg/kg-5 mg/kg of body weight; preferably therange is about 1 μg/kg-300 μg/kg of body weight; more preferably about10 μg/kg-100 μg/kg of body weight. For a typical 70-kg human subject,thus, the dosage range is from about 0.7 μg-350 mg; preferably about 700μg-21 mg; most preferably about 700 μg-7 mg. Dosages may be higher whenthe compounds are administered orally or transdermally as compared to,for example, i.v. administration.

The compounds may be administered as a single bolus dose, a dose overtime, as in i.v. or transdermal administration, or in multiple dosages.

In addition to direct administration to the subject, the compounds offormula (1) can be used in ex vivo treatment protocols to prepare cellcultures which are then used to replenish the blood cells of thesubject. Ex vivo treatment can be conducted on autologous cellsharvested from the peripheral blood or bone marrow or from allograftsfrom matched donors. The concentration of the compound or compounds offormula (1) alone or in combination with other agents, such asmacrophage inflammatory protein is a matter of routine optimization.

Subjects that will respond favorably to the method of the inventioninclude medical and veterinary subjects generally, including humanpatients. Among other subjects for whom the methods of the invention isuseful are cats, dogs, large animals, avians such as chickens, and thelike. In general, any subject who would benefit from an elevation ofprogenitor cells and/or stem cells, or whose progenitor cells and/orstem cells are desirable for stem cell transplantation are appropriatefor administration of the invention method.

Typical conditions which may be ameliorated or otherwise benefited bythe method of the invention include hematopoietic disorders, such asaplastic anemia, leukemias, drug-induced anemias, and hematopoieticdeficits from chemotherapy or radiation therapy. The method of theinvention is also useful in enhancing the success of transplantationduring and following immunosuppressive treatments as well as ineffecting more efficient wound healing and treatment of bacterialinflammation. The method of the present invention is further useful fortreating subjects who are immunocompromised or whose immune system isotherwise impaired. Typical conditions which are ameliorated orotherwise benefited by the method of the present invention, includethose subjects who are infected with a retrovirus and more specificallywho are infected with human immunodeficiency virus (HIV). The method ofthe invention thus targets a broad spectrum of conditions for whichelevation of progenitor cells and/or stem cells in a subject would bebeneficial or, where harvesting of progenitor cells and/or stem cell forsubsequent stem cell transplantation would be beneficial.

The invention compounds are also administered to regenerate myocardiumby mobilizing bone marrow stem cells.

Having now generally described the invention, the same will be morereadily understood through reference to the following examples which areprovided by way of illustration, and are not intended to be limiting ofthe present invention, unless specified.

EXAMPLE 1 Elevation of Mouse Progenitor Cell Levels

The effects of subcutaneous (s.c.) administration of1,1′-[1,4-phenylene-bis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane(AMD3100) to C3H/H3 J mice on numbers of granulocyte macrophage(CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitorcells per mL of blood were measured. Progenitors were stimulated to formcolonies in vitro with the combination of 1 U/ml rhu Epo, 50 ng/ml rhuSLF, 5% Vol/Vol pokeweed mitogen mouse spleen cell conditioned medium(PWMSCM), and 0.1 mM hemin. Plates were scored 7 days after incubation.

The time dependent effects on the number of progenitors mobilized withAMD3100 are for a single s.c. injection of 5 mg/Kg and are shown inTable 1. TABLE 1 Absolute Progenitors Per ML Blood MethylcelluloseCulture CFU-GM BFU-E CFU-GEMM Control 289.8 49.4 25.8 AMD3100 15″ 791.6134.5 90.4 AMD3100 30″ 1805.5 209.3 113.5 AMD3100 120″ 828.7 102.3 47.6

To measure the dose-dependent effects, AMD3100 was administered at 1,2.5, 5 and 10 mg/Kg via a single s.c. injection and the number ofprogenitors per mL of blood was measured at 1 hour post administration,and the results are shown in Table 2. TABLE 2 Absolute NumberProgenitors Per ML Blood Methylcellulose Culture CFU-GM BFU-E CFU-GEMMSaline 188.1 16 19 AMD3100 10 mg/kg 825.6 120.5 79.8 AMD3100 5 mg/kg608.4 92.8 69.5 AMD3100 2.5 mg/kg 687.6 98.9 70.6 AMD3100 1 mg/kg 424 6227.1

Fold Change Compared To Time 0 Progenitors Methylcellulose Culture TimeGM BFU-E CFU-GEMM 15″ 2.73 2.72 3.51 30″ 6.23 4.24 4.41  2′ 2.86 2.071.85

Maximum mobilization of mouse progenitors is achieved at a dose of 2.5to 10 mg/kg AMD3100, and was observed at 0.25 to 2 hours afterinjection, as shown in Table 2 above.

EXAMPLE 2 Mobilization of Mouse Progenitor Cells in Combination withMIP-1α and G-CSF

The progenitor cell mobilization capacity of AMD3100 in combination withmouse (mu) macrophage inflammatory protein (MIP-1α) was tested with orwithout prior administration of rhu G-CSF. MIP-1α: has been previouslyshown to mobilize progenitor cells in mice and humans (Broxmeyer, H. E.,et al., Blood Cells, Molecules, and Diseases (1998) 24(2):14-30).

Groups of mice were randomized to receive control diluent (saline) orG-CSF at a dose of 2.5 μg per mouse, twice a day, for two days via s.c.injection. Eleven hours after the final injection of saline or G-CSF,the mice were divided into groups to receive MIP-1α administered i.v. ata total dose of 5 μg, AMD3100 administered s.c. at a dose of 5 mg/Kg, ora combination of both MIP-1α and AMD3100 at the same doses. One hourlater, the mice were sacrificed and the number of progenitor cells permL of blood were measured. These data are summarized in FIG. 1.

AMD3100 acts in an additive to greater than additive manner formobilization of progenitor cells when used in combination with mouse(mu) macrophage inflammatory protein (MIP)-1α, each given 11 hours afterthe addition of rhu G-CSF or control diluent (saline) and 1 hour priorto assessing the blood.

EXAMPLE 3 Clinical Elevation of Progzenitor Cell Levels

Five healthy human volunteers having initial white blood cell counts of4,500-7,500 cells/mm³ were used in the study. Each patient was given asingle subcutaneous (s.c.) injection of 80 μg/kg AMD3100 (i.e.,1,1′-[1,4-phenylene-bis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane)in 0.9% saline, from a stock solution of 10 mg/mL AMD3100 in saline,under sterile conditions. Blood samples were obtained via catheter priorto the dose, and at various times up to 24 hours after dosing.

The blood samples were evaluated for total white blood cells, CD34positive progenitor cells (via FACS analysis) as a percentage of totalwhite blood cells, as well as the absolute numbers per mL and cyclingstatus of granulocyte macrophage (CFU-GM), erythroid (BFU-E), andmultipotential (CFU-GEMM) progenitor cells.

As shown in Tables 3 and 4, administration of AMD3100 caused anelevation of the white blood cell count and of CD34 positive progenitorcells in human volunteers which maximized at 6 hourspost-administration. TABLE 3 AMD3100 induced mobilization of white bloodcells in individual volunteers (×10³ WBC's). TREATMENT Base- 30 IDScreen line Min 1 Hr 2 Hr 4 Hr 6 Hr 9 Hr Day 2 P1 7.4 6.41 8.02 14.821.4 23.2 26.2 22.3 7.07 P2 6.04 5.45 6.53 8.93 13.5 18.00 19.2 19.68.03 P3 4.38 5.8 7.14 9.28 ND 18.10 17.9 18.4 4.98 P4 5.08 5.31 4.377.38 12.4 14.6 15.8 13.9 4.98 P5 4.53 5.02 6.08 8.43 ND 16.90 19.3 19.004.57

TABLE 4 AMD3100 induced mobilization of CD34 positive cells, expressedas the percentage of the total WBC's in individual volunteers. TREATMENTID Baseline 1 Hr 3 Hr 6 Hr 9 Hr Day 2 P1 .07 .04 .07 .11 .11 .08 P2 .08.06 .08 .13 .11 .12 P3 .07 .16 .06 ND .11 .07 P4 .05 .07 .09 .09 .1 .1P5 .12 .12 .13 .2 .2 .16

The blood was also analyzed for AMD3100 mobilized these progenitors.

Absolute numbers of unseparated and low density (Fico-hypaque separated)nucleated cells per ml of blood, as well as the absolute numbers per mland cycling status of granulocyte macrophage (CFU-GM), erythroid(BFU-E), and multipotential (CFU-GEMM) progenitor cells were measured innormal donors injected s.c. with AMD3100. The above parameters wereassessed prior to injection and at 1, 3, 6, 9 and 24 hours afterinjection of AMD3100. All progenitor cell results are based on thescoring of 3 culture plates per assay per point.

For the progenitor cell numbers and cycling status, the numbers ofCFU-GM, BFU-E and CFU-GEMM in methylcellulose cultures by stimulation ofthe cells with 1 Unit (U)/ml recombinant human (rhu) erythropoietin, 100U/ml rhu granulocyte-macrophage colony stimulating factor (GM-CSF), 100U/ml rhu interleukin-3 (IL-3) and 50 ng/ml rhu steel factor (SLF=stemcell factor (SCF)). The CFU-GM were also evaluated in agar culturesstimulated with 100 U/ml rhu GM-CSF and 50 ng/ml rhu SLF. For both typesof assays, colonies were scored after 14 day incubation in a humidifiedatmosphere with 5% CO₂ and lowered (5%) O₂ tension. Cell cycling statusof progenitors was measured using a high specific activity tritiatedthymidine kill technique as previously described (Broxmeyer, H. E., etal., Exp. Hematol. (1989) 17:455-459).

The results are given first, as the mean fold change in absolute numbersof nucleated cells and progenitors at 1, 3, 6, 9 and 24 hours comparedto the preinjection (=Time (T) 0) counts for all five donors, as seen inTables 5-7.

In the tables below,

STD—Standard deviation

STE—Standard error

PBL-US—peripheral blood-unseparated

PBL-LD—peripheral blood-low density (Ficoll Separated)

P—Significance using a 2 tailed t test TABLE 5 Fold Change Compared toTIME = 0 (Average of 5 donors) NUCLEATED CELLULARITY PBL-US PBL-LD MEANSTD STE % CHG P MEAN STD STE % CHG P T = 0 1.00 0.00 0.00 0.0% 1.00 0.000.00 0.0% T = 1 1.69 0.00 0.00 68.6% 0.017 1.86 0.00 0.00 86.2% 0.000 T= 3 2.80 0.51 0.23 180.2% 0.000 2.86 0.28 0.12 185.6% 0.000 T = 6 3.260.61 0.27 225.8% 0.000 3.66 0.43 0.19 266.3% 0.001 T = 9 3.09 0.69 0.31209.4% 0.000 3.64 1.18 0.53 264.3% 0.001 T = 24 1.07 0.65 0.29 7.0%0.553 1.05 1.19 0.53 4.6% 0.815

TABLE 6 METHYL CELLULOSE CULTURE CFU-GM BFU-E CFU-GEMM MEAN STD STE %CHG P MEAN STD STE % CHG P MEAN STD STE % CHG P T = 0 1.00 0.00 0.000.0% 1.00 0.00 0.00 0.0% 1.00 0.00 0.00 0.0% T = 1 4.77 0.00 0.00 376.7%0.001 1.99 0.00 0.00 98.9% 0.002 2.32 0.00 0.00 131.8% 0.000 T = 3 13.661.56 0.70 1266.5% 0.001 3.21 0.50 0.22 221.3% 0.004 4.33 0.44 0.20332.5% 0.000 T = 6 21.71 5.78 2.58 2070.6% 0.000 6.01 1.25 0.56 500.5%0.006 10.07 0.59 0.27 907.2% 0.002 T = 9 10.47 5.09 2.28 947.3% 0.0004.34 2.99 1.34 334.4% 0.000 5.25 4.54 2.03 425.4% 0.014 T = 24 1.56 3.011.34 55.5% 0.005 1.26 1.02 0.45 26.3% 0.194 1.53 3.04 1.36 53.2% 0.199

TABLE 7 AGAR CULTURE CFU-GM MEAN STD STE % CHG P T = 0 1.00 0.00 0.000.0% T = 1 2.81 0.00 0.00 180.8% 0.001 T = 3 8.54 0.75 0.34 754.1% 0.000T = 6 17.93 1.62 0.72 1692.8% 0.000 T = 9 10.25 4.57 2.04 924.9% 0.000 T= 24 2.08 2.06 1.03 108.3% 0.073

The results are then shown as a fold change from T=0 levels for eachindividual donor, as shown in Tables 8-10. TABLE 8 FOLD CHANGE COMPAREDTO TIME = 0 far each individual patient [P] NUCLEATED CELLULARITY PBL-USPBL-LD P1 P2 P3 P4 P5 P1 P2 P3 P4 P5 T = 0 1.00 1.00 1.00 1.00 1.00 1.001.00 1.00 1.00 1.00 T = 1 2.54 1.38 1.38 1.36 1.76 2.07 1.99 1.48 1.662.10 T = 3 3.55 2.74 2.02 2.46 3.23 2.83 3.25 2.17 2.82 3.20 T = 6 3.972.94 2.74 2.60 4.04 4.07 3.90 2.27 2.78 5.30 T = 9 3.27 3.30 2.69 2.243.96 3.65 4.43 2.47 2.48 5.17 T = 24 1.21 1.43 0.96 0.77 0.99 1.01 1.710.79 0.60 1.12

TABLE 9 PROGENITORS METHYL CELLULOSE CULTURE CFU-GM BFU-E CFU-GEMM P1 P2P3 P4 P5 P1 P2 P3 P4 P5 P1 P2 P3 P4 P5 T = 0 1.00 1.00 1.00 1.00 1.001.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 T = 1 5.09 5.33 3.706.87 2.84 2.58 1.48 2.30 1.48 2.13 2.07 2.26 2.22 1.96 3.07 T = 3 7.1217.02 15.07 20.72 8.40 5.13 1.98 2.61 2.60 3.75 4.25 3.47 4.34 5.14 4.43T = 6 14.66 23.96 20.99 28.54 20.39 9.14 3.67 4.54 3.34 9.35 7.47 9.356.52 9.10 17.92 T = 9 6.26 12.51 9.42 14.08 10.09 5.43 4.61 3.71 2.935.05 2.64 7.09 2.47 4.52 9.55 T = 24 1.10 1.91 1.43 1.51 1.83 1.06 1.881.14 0.79 1.44 1.12 2.62 0.69 0.98 2.25

TABLE 10 AGAR CULTURE CFU-GM P1 P2 P3 P4 P5 T = 0 1.00 1.00 1.00 1.001.00 T = 1 3.05 3.74 1.67 2.71 2.87 T = 3 8.88 9.49 7.47 10.46 6.40 T =6 17.77 24.01 14.04 13.07 20.75 T = 9 10.28 7.72 10.22 12.78 T = 24 3.691.13 1.30 2.20

The actual nucleated cell and progenitor cell numbers per ml of bloodand the cycling status (=% progenitors in DNA synthesis (S) phase of thecell cycle) of progenitors for each of the five donors (#'s P1, P2, P3,P4, and P5) is shown in Tables 11 and 12. TABLE 11 BFU-E CFU- BFU-E CFU-CFU-GM P1 GEMM CFU-GM P2 GEMM Absolute Cycling Absolute Cycling AbsoluteCycling Absolute Cycling Absolute Cycling Absolute Cycling # of Status #of Status # of Status # of Status # of Status # of Status Pro- of Pro-of Pro- of Pro- of Pro- of Pro- of genitors Pro- genitors Pro- genitorsPro- genitors Pro- genitors Pro- genitors Pro- per ML genitors per MLgenitors per ML genitors per ML genitors per ML genitors per ML genitorsT = 0 247 6% 261 0% 127 6% 273 0% 410 2% 120 0% T = 1 1259 1% 674 0% 2640% 1455 0% 608 3% 272 6% T = 3 1760 1% 1340 13% 540 7% 4646 2% 809 0%418 0% T = 6 3624 0% 2388 0% 949 0% 6540 0% 1502 0% 1126 0% T = 9 15472% 1418 11% 335 0% 3416 0% 1886 0% 854 4% T = 24 271 0% 278 0% 142 0%521 3% 768 2% 316 0% BFU-E CFU- BFU-E CFU- CFU-GM P3 GEMM CFU-GM P4 GEMMAbsolute Cycling Absolute Cycling Absolute Cycling Absolute CyclingAbsolute Cycling Absolute Cycling # of Status # of Status # of Status #of Status # of Status # of Status Pro- of Pro- of Pro- of Pro- of Pro-of Pro- of genitors Pro- genitors Pro- genitors Pro- genitors Pro-genitors Pro- genitors Pro- per ML genitors per ML genitors per MLgenitors per ML genitors per ML genitors per ML genitors T = 0 281 0%351 0% 140 0% 138 0% 460 0% 101 0% T = 1 1040 0% 806 0% 312 0% 947 0%672 0% 199 0% T = 3 4233 1% 915 0% 610 0% 2857 5% 1195 9% 519 0% T = 65895 0% 1593 0% 916 0% 3936 0% 1533 0% 920 8% T = 9 2647 0% 1302 0% 3470% 1942 0% 1348 0% 457 0% T = 24 402 0% 402 0% 97 0% 208 5% 362 3% 99 0%CFU-GM BFU-E P5 CFU-GEMM Absolute # Absolute # Absolute # of ProgenitorsCycling of Progenitors Cycling of Progenitors Cycling per ML Status ofProgenitors per ML Status of Progenitors per ML Status of Progenitors T= 0 169 0% 343 1% 55 0% T = 1 481 0% 730 0% 169 0% T = 3 1423 5% 1288 3%244 0% T = 6 3454 0% 3208 1% 987 0% T = 9 1710 0% 1731 0% 526 0% T = 24310 0% 495 0% 124 0%

TABLE 12 AGAR Culture AGAR Culture AGAR Culture AGAR Culture AGARCulture CFU-GM CFU-GM CFU-GM CFU-GM CFU-GM P1 P2 P3 P4 P5 AbsoluteCycling Absolute Cycling Absolute Cycling Absolute Cycling AbsoluteCycling # of Status # of Status # of Status # of Status # of StatusProgenitors of Pro- Progenitors of Pro- Progenitors of Pro- Progenitorsof Pro- Progenitors of Pro- per ML genitors per ML genitors per MLgenitors per ML genitors per ML genitors T = 0 233 6% 100 0% 140 0% 1240% 104 0% T = 1 710 0% 376 0% 234 0% 336 0% 298 3% T = 3 2070 0% 953 1%1049 0% 1299 0% 664 0% T = 6 4142 0% 2409 3% 1972 3% 1623 0% 2153 1% T =9 1032 0% 1085 0% 1268 0% 1326 0% T = 24 371 0% 159 0% 162 0% 229 0%

The results for all five donors were very consistent with maximal foldincreases in circulating levels of progenitor cells seen 6 hours afterinjection of AMD3100 into the human donor subjects. Progenitors were ina slow or non-cycling state prior to and 1, 3, 6, 9 and 24 hours afterinjection of AMD3100.

EXAMPLE 4 Mobilized Bone Marrow Stem Cells for Myocardial Repair

Adult rats are anesthetized and a thoracotomy is performed. Thedescending branch of the left coronary artery is ligated and notreperfused. Within 4 to 6 hours after ligation the animals are injectedwith limit dilution AMD3100 or AMD3100 plus rhG-CSF. Control rats arenot treated with the reagents. The animals are monitored at one-weekintervals by echocardiography and MRI. The experiment is terminated at2, 6 to 12 weeks post-surgery. On the day of sacrifice, the hemodynamicfunctions are analyzed for left ventricle-end diastolic pressure, leftventricle-developed pressure and the rate of rise and fall of leftventricle pressure. The heart is then arrested in diastole and perfusedvia the abdominal aorta to flush residual blood from the vascularnetwork of the myocardium. This is followed by perfusion of the heartwith 10% formalin. Several slices are made through the fixed heart andthese are embedded in paraffin and sections. The sections are stainedand analyzed by light microscopy to determine the size of the infarct inthe treated and control animals. Tissue sections from hearts taken at 2weeks after surgery are stained with antibodies specific for immature,developing myocyte and blood vessel proteins and analyzed by confocalmicroscopy. The immunohistochemical analysis involves the identificationof transcription factors and surface markers expressed in early stagesof myocyte development. The results of this experiment will show thatwhen the reagent AMD3100 is administered within hours after induction ofcardiac ischemia, together with or without rhG-CSF, this reagentmobilizes bone marrow stem cells rapidly, and will result in a block tocardiac remodeling and scar formation and will lead to regeneration ofthe dead myocardium.

1. A method to obtain progenitor and/or stem cells from a subject whichmethod comprises (a) administering to said subject a compound of theformulaZ-linker-Z′  (1) or pharmaceutically acceptable salt or prodrug formthereof wherein Z is a cyclic polyamine containing 9-32 ring members ofwhich 2-8 are nitrogen atoms, said nitrogen atoms separated from eachother by at least 2 carbon atoms, and wherein said heterocycle mayoptionally contain additional heteroatoms besides nitrogen and/or may befused to an additional ring system; or Z is of the formula

wherein A comprises a monocyclic or bicyclic fused ring systemcontaining at least one N and B is H or an organic moiety of 1-20 atoms,Z′ is either embodied in a form as defined by Z above, or is of theformula—N(R)—(CR₂)_(n)—X wherein each R is independently H or straight,branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring,including heteroaromatic rings, or is a mercaptan; “linker” represents abond, alkylene (1-6C) or may comprise aryl, fused aryl, and/or oxygenatoms contained in an alkylene chain, and/or may contain keto groupsand/or nitrogen or sulfur atoms; in an amount effective to mobilize saidprogenitor and/or stem cells into the peripheral blood of said subject;followed by (b) harvesting said progenitor and/or stem cells.
 2. Themethod of claim 1 wherein Z and Z′ are both cyclic polyamines.
 3. Themethod of claim 1 wherein Z and Z′ are identical.
 4. The method of claim1 wherein Z is a cyclic polyamine that contains 10-24 members andcontains 4 nitrogen atoms.
 5. The method of claim 3 wherein Z and Z′ areboth 1,4,8,11-tetraazocyclotetradecane.
 6. The method of claim 1 whereinthe linker comprises an aromatic ring bracketed by two methylenemoieties.
 7. The method of claim 6 wherein the linker is1,4-phenylene-bis-methylene.
 8. The method of claim 7 wherein thecompound of formula (1) is1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane.9. The method of claim 4 wherein Z′ is—N(R)—(CR₂)_(n)—X wherein each R, N and X are as defined in claim
 1. 10.The method of claim 9 wherein the linker is1,4-phenylene-bis-(methylene).
 11. The method of claim 10 wherein Z′ is2-aminomethyl-pyridine.
 12. The method of claim 11 wherein the compoundof formula (1) isN[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylene-bis-(methylene)]-2-aminomethyl-pyridine.13. The method of claim 1 wherein Z is of the formula

wherein A comprises a monocyclic or bicyclic fused ring systemcontaining at least one N and B is H or an organic moiety of 1-20 atoms.14. The method of claim 1 wherein formula (1) is in the form of its acidaddition salt.
 15. The method of claim 14 wherein the acid addition saltis hydrochloride.
 16. The method of claim 1 wherein the compound isadministered to said subject by an intravenous or subcutaneous route.17. The method of claim 1 wherein the compound of formula (1) isadministered to said subject in the dosage range of about 0.1 μg/kg-5mg/kg of body weight.
 18. The method of claim 1 which further comprisesadministering macrophage inflammatory protein to said subject.
 19. Themethod of claim 1 which further comprises administering G-CSF to saidsubject prior to performing said method.
 20. The method of claim 1wherein the subject is human.
 21. The method of claim 8 wherein formula(1) is in the form of its acid addition salt.
 22. The method of claim 21wherein the acid addition salt is hydrochloride.
 23. The method of claim8 wherein the compound is administered to said subject by an intravenousor subcutaneous route.
 24. The method of claim 8 wherein the compound offormula (1) is administered to said subject in the dosage range of about0.1 μg/kg-5 mg/kg of body weight.
 25. The method of claim 8 whichfurther comprises administering macrophage inflammatory protein to saidsubject.
 26. The method of claim 8 which further comprises administeringG-CSF to said subject prior to performing said method.
 27. The method ofclaim 8 wherein the subject is human.
 28. A method to obtain progenitorand/or stem cells from a subject which method comprises (a)administering to said subject an amount of a compound that binds to thechemokine receptor CXCR4 sufficient to mobilize said progenitor and/orstem cells into the peripheral blood of said subject; followed by (b)harvesting said progenitor and/or stem cells.